title: Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation.
abstract: Fractalkine, a chemokine anchored to neurons or peripheral endothelial cells, serves as an adhesion molecule or as a soluble chemoattractant. Fractalkine binds CX3CR1 on microglia and circulating monocytes, dendritic cells, and NK cells. The aim of this study is to determine the role of CX3CR1 in the trafficking and function of myeloid cells to the CNS during experimental autoimmune encephalomyelitis (EAE). Our results show that, in models of active EAE, Cx3cr1(-/-) mice exhibited more severe neurologic deficiencies. Bone marrow chimeric mice confirmed that CX3CR1 deficiency in bone marrow enhanced EAE severity. Notably, CX3CR1 deficiency was associated with an increased accumulation of CD115(+)Ly6C(-)CD11c(+) dendritic cells into EAE-affected brains that correlated with enhanced demyelination and neuronal damage. Furthermore, higher IFN-γ and IL-17 levels were detected in cerebellar and spinal cord tissues of CX3CR1-deficient mice. Analyses of peripheral responses during disease initiation revealed a higher frequency of IFN-γ- and IL-17-producing T cells in lymphoid tissues of CX3CR1-deficient as well as enhanced T cell proliferation induced by CX3CR1-deficient dendritic cells. In addition, adoptive transfer of myelin oligodendrocyte glycoprotein35-55-reactive wild-type T cells induced substantially more severe EAE in CX3CR1-deficient recipients when compared with wild-type recipients. Collectively, the data demonstrate that besides its role in chemoattraction, CX3CR1 is a key regulator of myeloid cell activation contributing to the establishment of adaptive immune responses.
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, USA.
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Garcia
authors.forename: Paula A
authors.initials: PA
authors.lastname: Pino
authors.forename: Makiko
authors.initials: M
authors.lastname: Mizutani
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardona
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Forsthuber
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Cardona
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D015551:Autoimmunity; D001854:Bone Marrow Cells; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D049109:Cell Proliferation; D002490:Central Nervous System / Q000166:cytology; D002678:Chimera; D003711:Demyelinating Diseases / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000276:immunology / Q000378:metabolism*; D015728:Receptors, HIV / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D039521:CD11c Antigen; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D007375:Interleukin-1; D020381:Interleukin-17; C494192:Ly-6C antigen, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015728:Receptors, HIV; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; D016186:Receptor, Macrophage Colony-Stimulating Factor